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Intra- and inter-cellular signals that drive hepato-oncogenesis

驱动肝肿瘤发生的细胞内和细胞间信号

基本信息

批准号：
10557925
负责人：
Gen-Sheng Feng
金额：
$ 41.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-10 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557925
关键词：
Ablation Animal Model Automobile Driving BAY 54-9085 Cells Cessation of life Chemicals Clinical Complement Data Diethylnitrosamine Disease Environment Environmental Risk Factor Epidermal Growth Factor Receptor Excision Goals Hepatic Hepatocarcinogenesis Hepatocyte Human Immunotherapy Liver Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Modeling Molecular Mus NF-kappa B Oncogenes Oncogenic Oncoproteins Oxidative Stress PIK3CA gene Paper Pathogenicity Pathway interactions Patients Pharmacologic Substance Pharmacy (field)Phenotype Play Primary carcinoma of the liver cells Process Proteins Publishing Research Role Sampling Signal Pathway Signal Transduction Sister TP53 gene Testing Therapeutic Transfection Tumor Promotion Tumor Suppressor Proteins beta catenin cancer type chemical carcinogen design experimental study genetic analysis interdisciplinary approach kinase inhibitor liver cancer model liver cancer patient liver inflammation liver injury mouse model novel novel therapeutic intervention single-cell RNA sequencing theories therapeutically effective tumor tumorigenesis tumorigenic

项目摘要

Liver cancer, mainly hepatocellular carcinoma (HCC), has become a most deadly malignant disease worldwide. So far, pharmaceutic inhibition of major oncogenic pathways has achieved little therapeutic benefit to liver cancer patients. We believe this is due to under- appreciation of the complexity in mechanisms of hepato-oncogenesis. In recent experiments, we and others have identified paradoxically anti-oncogenic effects of classical oncogenic molecules, such as c-Met, EGFR, β-catenin, Ikkβ, Jnk, and Shp2, in the liver. Ablating these molecules in hepatocytes enhanced HCC induced by chemical carcinogen DEN. To test a theory that loss of the oncogenic molecules generates an oncogenic microenvironment that promotes DEN-induced HCC, we have established another mouse HCC model, by transfection of oncogenic β-catenin (CAT), c-Met (MET) and PIK3CA (PIK), oncoproteins frequently detected in human HCCs. As expected, MET/CAT-driven HCC was aggravated in β-catenin-deficient liver, due to tumor-promoting factors induced by β-catenin removal. In contrast, Shp2 deletion dramatically suppressed HCC driven by MET/CAT or MET/PIK, despite a similar pro-tumorigenic environment in Shp2-deficient liver. Based on these novel unanticipated data, we propose a new hypothesis that although removal of Shp2 or β-catenin generates cell-extrinsic tumorigenic factors in the hepatic environment, the endogenous Shp2 is indispensable for oncogenic signaling in hepatocytes. To test this hypothesis, we propose three specific aims on this project. Aim 1 is to determine the cell-intrinsic role of Shp2 in hepato-oncogenic signaling. Aim 2 is to determine the cell-autonomous effect of β-catenin in liver tumorigenesis. Aim 3 is to search and identify cell-extrinsic factors induced by loss of the oncoproteins in hepatocytes. The results are expected to be instrumental for design of novel therapeutic strategies for liver cancer by inhibiting both cell-intrinsic oncogenic signals and the secondary environmental factors.

肝癌，主要是肝细胞癌（HCC），已成为最致命的癌症